Synthesis of Chiral Tertiary Allylic- and Propargylic Fluorides from Nonaflates of Chiral α-Fluorinated ß-Keto Dicarbonyl Compounds.

The acetyl group of chiral α-fluorinated dicarbonyl compounds was transformed to nonaflates through a reaction with perfluorobutanesulfonyl fluoride in the presence of DBU in 82-95% yield. These nonaflates were used in Suzuki and Sonogashira coupling reactions to afford chiral tertiary allylic fluorides bearing gem-disubstituted terminal alkenes with excellent optical purities (45-91%, ≥94% ee). In addition, chiral tertiary propargylic fluorides were obtained from the reaction of nonaflates with DBU (73-86%, ≥94% ee).

Quantitative Chemical Analysis of Defensive Secretion of Megacrania tsudai (Phasmatidae) and Effect of Actinidine on its Potential Predators.

Insects avoid predation in various ways, and some use multiple ways to avoid predation. However, the effects of comprehensive avoidance methods and the differences in avoidance methods among different life stages of insects have not been sufficiently discussed. The big head stick insect Megacrania tsudai uses background matching as its primary defense and chemical defense as its secondary defense. The aims of this study were to identify and isolate the chemical components of M. tsudai using repeatable methods, determine the amount of the main chemical compound, and reveal the effect of the main chemical compound on its predators. We established a repeatable gas chromatography-mass spectrometry (GC-MS) method to identify the chemical compounds of these secretions, and identified actinidine as the main compound. Actinidine was identified by nuclear magnetic resonance (NMR), and the amount of actinidine in each instar was calculated by constructing a calibration curve using pure actinidine. Mass ratios did not drastically change among instars. Furthermore, experiments involving dropping an aqueous solution of actinidine demonstrated removal behavior in geckos, frogs, and spiders. These results indicated that M. tsudai conducts secondary defenses using defensive secretions consisting mainly of actinidine.

Alkali Carbonates Improve ß,ß-Diaryl Serine-Catalyzed Enantioselective α-Fluorination of ß-Dicarbonyl Compounds.

Herein, we report the highly enantioselective α-fluorination of both cyclic and acyclic ß-dicarbonyl compounds, including ß-diketones, ß-ketoesters, and ß-ketoamides. The reactions with ß,ß-diaryl serines as primary amine organocatalysts were enhanced by adding alkali carbonates, such as Na2CO3 or Li2CO3, and enabled the reaction to be conducted with only 1.1 equiv of Selectfluor. The optimal conditions afforded the α-fluorinated ß-dicarbonyl compounds in 50-99% yield with excellent enantioselectivity (up to 98% ee).

Syntheses and Synthetic Applications of Functionalized Propargylic and Allylic Fluorides.

This account presents the synthesis and application of propargylic and allylic fluorides containing hydroxy or carbonyl functional groups. In particular, the Barbier-type reaction of difluoropropargyl bromides with aldehydes or chloroformates provides versatile propargylic fluorides, and the organocatalytic fluorination of dienamine intermediates has been demonstrated as an effective method to obtain allylic fluorides stereoselectively. Additionally, mechanistic insights into such reactions are discussed with the aid of density functional theory calculations. The report also describes the preparation of fluorinated 1,7-diyne or 1,7-enyne derivatives of these compounds. These propargylic and allylic fluorides can be used as building blocks for fluorinated heterocycles, such as fluorinated furans, tetrahydrofurans, and lactams. Additionally, fluorinated bi- or tri-heterocyclic compounds can be synthesized via transition-metal-catalyzed reactions with fluorinated 1,7-diyne or 1,7-enyne derivatives.

Enantioselective Fluorination of α-Substituted ß-Diketones Using ß,ß-Diaryl Serines.

We report the enantioselective fluorination of α-substituted ß-diketones using ß,ß-diaryl serines as a primary amine organocatalyst. The reaction affords the corresponding fluorinated products in yields of 74 to 99% with excellent enantioselectivity (75-95% ee). Moreover, for synthetic applications, the diol, aldols, and the allylic fluoride were synthesized from 2a, maintaining excellent enantioselectivity (94% ee). The control experiment reveals that the CO2H group of the ß,ß-diaryl serines plays an important role in inducing the high enantioselectivity.

One-pot synthesis of new alkyl 1-naphthoates bearing quinoline, pyranone and cyclohexenone moieties via metal-free sequential addition/oxidation reactions.

A mild and one-pot synthetic pathway was successfully developed for the synthesis of new naphthoate-based scaffolds containing quinoline, pyranone and cyclohexenone moieties via a multistep reaction between acenaphthoquinone and various 1,3-diketones in the presence of different primary aliphatic and benzylic alcohols. This reaction proceeds via a sequential addition/oxidation mechanistic process including a metal-free addition step of acenaphthoquinone and 1,3-diketones followed by the H5IO6-mediated C-C oxidative cleavage of the corresponding vicinal diols at room temperature. The alcohols play a dual role, as the reaction solvent as well as the nucleophile, to conduct the reaction process toward naphthoate formation. All alkyl naphthoate derivatives prepared in this work are new compounds and were definitively characterized using 1H-NMR, 13C-NMR and HRMS analysis, while X-ray crystallography was carried out for one of the products. The synthesis of a naphthalene-based nucleus attached to heterocyclic moieties is noteworthy to follow in the near future for diverse applications in biology, medicine, metal complex design, and semiconductor and optical materials.

Enantioselective Fluorination of α-Branched ß-Ynone Esters Using a Cinchona-Based Phase-Transfer Catalyst.

Herein, we report the fluorination of α-branched ß-ynone esters to afford their corresponding quaternary fluorinated products with good enantioselectivity (ee = 73-90%) using a cinchona-based phase-transfer catalyst. α-Branched ß-ynone esters possess a highly acidic α-proton and form their corresponding enolate as a single isomer, which allows the enantioselective fluorination reaction to occur under standard cinchona-based phase-transfer catalyst conditions. Moreover, the obtained α-fluorinated product can be treated with [(SPhos)AuNTf2] (1 mol %) to afford a fluorinated 3,5-diketo carboxylic acid.

One-Pot Synthesis of Spiro-isobenzofuran Compounds via the Sequential Condensation/Oxidation Reaction of Ninhydrin with 4-Amino-1,2-naphthoquinones/2-Amino-1,4-naphthoquinones under Mild Conditions.

A one-pot route for the synthesis of spiro-isobenzofuran compounds was developed via the condensation reaction of ninhydrin with 4-amino-1,2-naphthoquinones or 2-amino-1,4-naphthoquinones in acetic acid followed by the oxidative cleavage of the corresponding vicinal diols at room temperature. Various derivatives of spiro[benzo[g]indole-2,1'-isobenzofuran]-3,3',4,5(1H) tetraones and spiro[benzo[f]pyrrolo[2,3-h]quinoxaline-2,1'-isobenzofuran]-3,3'(1H)-diones were synthesized in good to high yields. Moreover, further condensation of spiro[benzo[g]indole-2,1'-isobenzofuran]-3,3',4,5(1H)-tetraones with 1,2-diamines resulted in the new spiro-isobenzofuran compounds having phenazine rings in high yields.

Metal-free syntheses of new azocines via addition reactions of enaminones with acenaphthoquinone followed by oxidative cleavages of the corresponding vicinal diols.

A one-pot, clean and green procedure is described for the syntheses of new azocine derivatives via addition reactions of enaminones with acenaphthoquinone followed by periodic acid-mediated oxidative cleavages of the corresponding vicinal diols. Various derivatives of azocine were prepared and well characterized. The excellent yields, simple synthesis procedure, lack of a need to carry out any tedious work-up and column chromatography, metal-free catalysis, and mild reaction conditions are important features of this protocol.

Effects of Water Addition on a Catalytic Fluorination of Dienamine.

We investigate the effects of water addition on a highly stereocontrolled fluorination of dienamine generated by α-branched enals and 6'-hydroxy-9-amino-9-deoxy-epi-quinidine with N-fluorobenzenesulfonimide (NFSI) in the presence of Brønsted acid both experimentally and theoretically. It is experimentally found that water addition to organic solvent significantly shortens the reaction time whereas excessive water addition decreases the enantiomeric excess. The results calculated with three-dimensional reference interaction site model self-consistent field (3D-RISM-SCF) method are in good agreement with the experimental ones. It is revealed that the shortness of reaction time is caused by the reactant destabilization and that the decrease in enantiomeric excess is due to the difference of hydration free energy between two transition states.

Stereoselective Organocatalytic Synthesis of α,α-Difluoro-γ,γ-Disubstituted Butenals.

A highly stereoselective reaction of α,α-difluoro-γ,γ-disubstituted butenals 2 bearing two different substituents at the γ position has been developed with an organocatalytic system of l-proline (30 mol %) and salicylic acid (60 mol %). This novel reaction demonstrated a wide substrate scope and excellent E stereoselectivity in most cases. The obtained difluorinated aldehyde 2a was applied as a useful synthetic precursor for constructing 3,3-disubstituted allylic difluoride moieties.

A base-free neutral phase-transfer reaction system.

Although phase-transfer reactions catalyzed by using quaternary ammonium salts are generally believed to require base additives, we discovered that, even without any base additives, conjugate additions of 3-substituted oxindoles to nitroolefins proceeded smoothly in the presence of lipophilic quaternary ammonium bromide under water-organic biphasic conditions. The mechanism of this novel base-free neutral phase-transfer reaction system is investigated and the assumed catalytic cycle is presented together with interesting effects of water and lipophilicity of the phase-transfer catalyst. The base-free neutral phase-transfer reaction system can be applied to highly enantioselective conjugate addition and aldol reactions under the influence of chiral bifunctional ammonium bromides as key catalysts. The structure of the chiral ammonium enolate intermediate is discussed based on the single-crystal X-ray structures of relevant ammonium salts and the importance of bifunctional design of catalyst is clearly explained in the model of intermediate.

Design of structurally rigid trans-diamine-based Tf-amide organocatalysts with a dihydroanthracene framework for asymmetric conjugate additions of heterosubstituted aldehydes to vinyl sulfones.

Asymmetric conjugate addition of α-heterosubstituted aldehydes such as α-amido and α-alkoxy aldehydes to vinyl sulfone was effected under the influence of structurally rigid trans-diamine-based Tf-amido organocatalyst (S,S)-2 with a dihydroanthracene framework to furnish α,α-dialkyl(amido)aldehydes and α,α-dialkyl(alkoxy)aldehydes with high enantioselectivity. The chiral efficiency of the structurally unique catalyst (S,S)-2 is apparent in comparison with (S,S)-1 and (S,S)-4 with similar functionality.

Synthesis of fluorinated δ-lactams via cycloisomerization of gem-difluoropropargyl amides.

gem-Difluoro-1,7-enyne amides are suitable building blocks for the synthesis of difluorodihydropyridinones via a ring-closing metathesis reaction, and of 4,4-difluoro-3-oxoisoquinolines through a ring-closing metathesis-enyne metathesis tandem reaction. These products, in turn, undergo a Diels-Alder reaction to yield heterotricyclic systems in moderate to good yields.

Concise preparation of 2,2-difluorohomopropargyl carbonyl derivatives. Application to the synthesis of 4,4-difluoroisoquinolinone congeners.

A scalable synthesis of 2,2-difluorohomopropargyl esters was achieved using a magnesium-promoted Barbier reaction of substituted difluoropropargyl bromides with alkyl chloroformates. These 2,2-difluorohomopropargyl esters were effective precursors in the synthesis of homopropargylic amides-by aminolysis using AlMe3, as well as of ketones-through the reaction of the corresponding Weinreb amides with Grignard reagents. Ring closing metathesis using difluorinated 1,7-enyne carbonyl compounds furnished six-membered diene products, which were used as susbstrates in a Diels-Alder reaction to afford 4,4-difluoroisoquinolin-3-ones. The [2 + 2 + 2] cycloaddition of alkynes with fluorinated 1,7-diyne amides gave 4,4-difluoro-1,4-dihydro-3(2H)-isoquinolinone derivatives regioselectively.

Synthesis of 2,4,5-trisubstituted 3-fluorofurans via sequential iodocyclization and cross-coupling of gem-difluorohomopropargyl alcohols.

The iodocyclization of gem-difluorohomoallenyl and gem-difluorohomopropargyl alcohols with I2 and ICl, respectively, produced the corresponding fluorinated iodofuran analogues in good yields. The iodo substituent in fluorinated 4-iodofurans was utilized as a synthetic handle to prepare multi-substituted 3-fluorofurans using a Suzuki cross-coupling reaction. The yields of both iodocyclization of gem-difluorohomopropargyl alcohol and subsequent Suzuki coupling were dramatically enhanced by microwave irradiation.

Selective synthesis of fluorinated furan derivatives via AgNO3-catalyzed activation of an electronically deficient triple bond.

The transition metal-catalyzed direct activation of electron deficient triple bonds was investigated by using the combined electron withdrawing effects of two fluorine atoms to modulate the electronic density of the triple bond. With use of catalytic amounts of AgNO3 (10 mol %) the synthesis of substituted 3,3-difluoro-4,5-dihydrofurans from gem-difluorohomopropargyl alcohols occurred in excellent NMR yields. Treatment of these dihydrofurans with SiO2 or Pd/H2 yielded the corresponding 3-fluorinated furans and 3,3-difluorotetrahydrofurans.

Intramolecular hydroamination of difluoropropargyl amides: regioselective synthesis of fluorinated beta- and gamma-lactams.

Functionalized gem-difluoro beta- and gamma-lactams were synthesized through a novel intramolecular hydroamination reaction of difluoropropargyl amides. beta-Lactams were obtained via a Baldwin disfavored 4-exo-digonal cyclization using palladium acetate as the catalyst, whereas gamma-lactams were produced under basic conditions. Acid hydration of gamma-lactams produced ketoamides or hemiaminals selectively.

Lanthanide triflate-catalyzed preparation of beta,beta-difluorohomopropargyl alcohols in aqueous media. Application to the synthesis of 4,4-difluoroisochromans.

An indium-mediated Barbier-type reaction of difluoropropargyl bromide with several aldehydes in aqueous media was enhanced by a catalytic amount of a lanthanide triflate (5 mol %). The reaction gave the corresponding beta,beta-difluorohomopropargyl alcohols with high regioselectivity. The [2 + 2 + 2] alkyne cyclotrimerization of beta,beta-difluorohomopropargyl alcohols with monosubstituted acetylenes produced 4,4-difluoroisochromans in good yields with moderate regioselectivity.